Alzheimer's disease genetics converges on microglial and neuronal dysregulation.

Multi-ancestry analysis of 109,479 AD cases and 2,131,799 controls identifies 118 loci plus 9 ancestry-specific loci, including 48 new AD risk loci.

• Why it matters: Low single-SNP heritability estimates have suggested limited remaining common-variant risk, leaving AD genetic mechanisms and drug targets incompletely defined.
• What they did: The study analyzed 109,479 cases, 74,141 proxy cases, 2,131,799 controls, and 499,708 proxy controls, then tested microglia-upregulated and neuron-downregulated genes for enrichment and improved polygenic prediction.
• The result: SNP heritability is estimated at 16%, nearly threefold higher than previous estimates, and microglial/neuronal dysregulation gene sets are enriched for AD-associated genetic risk, enabling new mechanisms and drug targets.